Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module

Laura Di Magno; Simona Manni; Fiorella Di Pastena; Sonia Coni; Alberto Macone; Sara Cairoli; Manolo Sambucci; Paola Infante; Marta Moretti; Marialaura Petroni; Carmine Nicoletti; Carlo Capalbo; Enrico De Smaele; Lucia Di Marcotullio; Giuseppe Giannini; Luca Battistini; Bianca Maria Goffredo; Egidio Iorio; Enzo Agostinelli; Marella Maroder; Gianluca Canettieri

doi:10.1016/j.celrep.2020.01.024

Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module

Cell Rep. 2020 Feb 11;30(6):1735-1752.e7. doi: 10.1016/j.celrep.2020.01.024.

Authors

Laura Di Magno¹, Simona Manni², Fiorella Di Pastena², Sonia Coni², Alberto Macone³, Sara Cairoli⁴, Manolo Sambucci⁵, Paola Infante¹, Marta Moretti², Marialaura Petroni², Carmine Nicoletti⁶, Carlo Capalbo², Enrico De Smaele⁷, Lucia Di Marcotullio⁸, Giuseppe Giannini², Luca Battistini⁵, Bianca Maria Goffredo⁴, Egidio Iorio⁹, Enzo Agostinelli¹⁰, Marella Maroder², Gianluca Canettieri¹¹

Affiliations

¹ Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy.
² Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
³ Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, 00185 Rome, Italy.
⁴ Division of Metabolism and Research Unit of metabolic Biochemistry, Children's Hospital and Research Institute Bambino Gesù IRCCS, 00146 Rome, Italy.
⁵ IRCCS Santa Lucia Foundation, Neuroimmunology Unit, 00143 Rome, Italy.
⁶ Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University of Rome, 00161 Rome, Italy.
⁷ Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
⁸ Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, 00161 Rome, Italy.
⁹ Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy.
¹⁰ Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, 00185 Rome, Italy; International Polyamines Foundation-ONLUS, 00159 Rome, Italy.
¹¹ Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, 00161 Rome, Italy; International Polyamines Foundation-ONLUS, 00159 Rome, Italy. Electronic address: gianluca.canettieri@uniroma1.it.

PMID: 32049007
DOI: 10.1016/j.celrep.2020.01.024

Abstract

The antidiabetic drug phenformin displays potent anticancer activity in different tumors, but its mechanism of action remains elusive. Using Shh medulloblastoma as model, we show here that at clinically relevant concentrations, phenformin elicits a significant therapeutic effect through a redox-dependent but complex I-independent mechanism. Phenformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), a component of the glycerophosphate shuttle, and causes elevations of intracellular NADH content. Inhibition of mGPD mimics phenformin action and promotes an association between corepressor CtBP2 and Gli1, thereby inhibiting Hh transcriptional output and tumor growth. Because ablation of CtBP2 abrogates the therapeutic effect of phenformin in mice, these data illustrate a biguanide-mediated redox/corepressor interplay, which may represent a relevant target for tumor therapy.

Keywords: CtBP2; Hedgehog; NADH; biguanides; cancer; complex I; mGPD; metformin; phenformin; redox.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Co-Repressor Proteins / drug effects*
Hedgehog Proteins / drug effects*
Humans
Hypoglycemic Agents / pharmacology
Hypoglycemic Agents / therapeutic use*
Mice
Neoplasms / drug therapy*
Phenformin / pharmacology
Phenformin / therapeutic use*

Substances

Antineoplastic Agents
Co-Repressor Proteins
Hedgehog Proteins
Hypoglycemic Agents
Phenformin